Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes

Soyon Hong, Beth L. Ostaszewski, Ting Yang, Tiernan T. O'Malley, Ming Jin, Katsuhiko Yanagisawa, Shaomin Li, Tim Bartels, Dennis J. Selkoe

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, andits levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.

Original languageEnglish (US)
Pages (from-to)308-319
Number of pages12
JournalNeuron
Volume82
Issue number2
DOIs
StatePublished - Apr 16 2014
Externally publishedYes

Fingerprint

G(M1) Ganglioside
Membranes
Brain
Extracellular Fluid
N-Acetylneuraminic Acid
Transgenic Mice
Alzheimer Disease
Biomarkers
Lipids

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hong, S., Ostaszewski, B. L., Yang, T., O'Malley, T. T., Jin, M., Yanagisawa, K., ... Selkoe, D. J. (2014). Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron, 82(2), 308-319. https://doi.org/10.1016/j.neuron.2014.02.027

Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. / Hong, Soyon; Ostaszewski, Beth L.; Yang, Ting; O'Malley, Tiernan T.; Jin, Ming; Yanagisawa, Katsuhiko; Li, Shaomin; Bartels, Tim; Selkoe, Dennis J.

In: Neuron, Vol. 82, No. 2, 16.04.2014, p. 308-319.

Research output: Contribution to journalArticle

Hong, S, Ostaszewski, BL, Yang, T, O'Malley, TT, Jin, M, Yanagisawa, K, Li, S, Bartels, T & Selkoe, DJ 2014, 'Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes', Neuron, vol. 82, no. 2, pp. 308-319. https://doi.org/10.1016/j.neuron.2014.02.027
Hong, Soyon ; Ostaszewski, Beth L. ; Yang, Ting ; O'Malley, Tiernan T. ; Jin, Ming ; Yanagisawa, Katsuhiko ; Li, Shaomin ; Bartels, Tim ; Selkoe, Dennis J. / Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. In: Neuron. 2014 ; Vol. 82, No. 2. pp. 308-319.
@article{ac07a3a11364410596715f2fa0bd6b9f,
title = "Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes",
abstract = "Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, andits levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.",
author = "Soyon Hong and Ostaszewski, {Beth L.} and Ting Yang and O'Malley, {Tiernan T.} and Ming Jin and Katsuhiko Yanagisawa and Shaomin Li and Tim Bartels and Selkoe, {Dennis J.}",
year = "2014",
month = "4",
day = "16",
doi = "10.1016/j.neuron.2014.02.027",
language = "English (US)",
volume = "82",
pages = "308--319",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes

AU - Hong, Soyon

AU - Ostaszewski, Beth L.

AU - Yang, Ting

AU - O'Malley, Tiernan T.

AU - Jin, Ming

AU - Yanagisawa, Katsuhiko

AU - Li, Shaomin

AU - Bartels, Tim

AU - Selkoe, Dennis J.

PY - 2014/4/16

Y1 - 2014/4/16

N2 - Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, andits levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.

AB - Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics invivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than nontoxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, andits levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.

UR - http://www.scopus.com/inward/record.url?scp=84899068704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899068704&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2014.02.027

DO - 10.1016/j.neuron.2014.02.027

M3 - Article

C2 - 24685176

AN - SCOPUS:84899068704

VL - 82

SP - 308

EP - 319

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 2

ER -